Type i hypersensitivity ii,iii,iv

TYPE I HYPERSENSITIVITY

Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. The reaction may involve skin (urticaria and eczema), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis). The reaction may cause a range of symptoms from minor inconvenience to death. The reaction usually takes 15 - 30 minutes from the time of exposure to the antigen, although sometimes it may have a delayed onset (10 - 12 hours).

Immediate hypersensitivity is mediated by IgE. The primary cellular component in this hypersensitivity is the mast cell or basophil. The reaction is amplified and/or modified by platelets, neutrophils and eosinophils. A biopsy of the reaction site demonstrates mainly mast cells and eosinophils.

The mechanism of reaction involves preferential production of IgE, in response to certain antigens (often called allergens). The precise mechanism as to why some individuals are more prone to type-I hypersensitivity is not clear. However, it has been shown that such individuals preferentially produce more of TH2 cells that secrete IL-4, IL-5 and IL-13 which in turn favor IgE class switch. IgE has very high affinity for its receptor (Fcε; CD23) on mast cells and basophils.

A subsequent exposure to the same allergen cross links the cell-bound IgE and triggers the release of various pharmacologically active substances (figure 1). Cross-linking of IgE Fc-receptor is important in mast cell triggering. Mast cell degranulation is preceded by increased Ca++ influx, which is a crucial process; ionophores which increase cytoplasmic Ca++ also promote degranulation, whereas, agents which deplete cytoplasmic Ca++ suppress degranulation.

The agents released from mast cells and their effects are listed in Table 1. Mast cells may be triggered by other stimuli such as exercise, emotional stress, chemicals (e.g., photographic developing medium, calcium ionophores, codeine, etc.), anaphylotoxins (e.g., C4a, C3a, C5a, etc.). These reactions, mediated by agents without IgE-allergen interaction, are not hypersensitivity reactions, although they produce the same symptoms.

The reaction is amplified by PAF (platelet activation factor) which causes platelet aggregation and release of histamine, heparin and vasoactive amines. Eosinophil chemotactic factor of anaphylaxis (ECF-A) and neutrophil chemotactic factors attract eosinophils and neutrophils, respectively, which release various hydrolytic enzymes that cause necrosis. Eosinophils may also control the local reaction by releasing arylsulphatase, histaminase, phospholipase-D and prostaglandin-E, although this role of eosinophils is now in question.

Cyclic nucleotides appear to play a significant role in the modulation of immediate hypersensitivity reaction, although their exact function is ill understood. Substances which alter cAMP and cGMP levels significantly alter the allergic symptoms. Thus, substances that increase intracellular cAMP seem to relieve allergic symptoms, particularly broncho-pulmonary ones, and are used therapeutically (Table 2). Conversely, agents which decrease cAMP or stimulate cGMP aggravate these allergic conditions.

TYPE II HYPERSENSITIVITY

Type II hypersensitivity is also known as cytotoxic hypersensitivity and may affect a variety of organs and tissues. The antigens are normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II hypersensitivity. Drug-induced hemolytic anemia, granulocytopenia and thrombocytopenia are such examples. The reaction time is minutes to hours. Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG classes and complement (Figure 2). Phagocytes and K cells may also play a role.

The lesion contains antibody, complement and neutrophils. Diagnostic tests include detection of circulating antibody against the tissues involved and the presence of antibody and complement in the lesion (biopsy) by immunofluorescence. The staining pattern is normally smooth and linear, such as that seen in Goodpasture's nephritis (renal and lung basement membrane) (figure 3A) and pemphigus (skin intercellular protein, desmosome) (figure 3B).

Treatment involves anti-inflammatory and immunosuppressive agents.

TYPE III HYPERSENSITIVITY

Type III hypersensitivity is also known as immune complex hypersensitivity. The reaction may be general (e.g., serum sickness) or may involve individual organs including skin (e.g., systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis), lungs (e.g., aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis) or other organs. This reaction may be the pathogenic mechanism of diseases caused by many microorganisms.

The reaction may take 3 - 10 hours after exposure to the antigen (as in Arthus reaction). It is mediated by soluble immune complexes. They are mostly of the IgG class, although IgM may also be involved. The antigen may be exogenous (chronic bacterial, viral or parasitic infections), or endogenous (non-organ specific autoimmunity: e.g., systemic lupus erythematosus, SLE). The antigen is soluble and not attached to the organ involved. Primary components are soluble immune complexes and complement (C3a, 4a and 5a). The damage is caused by platelets and neutrophils (Figure 4). The lesion contains primarily neutrophils and deposits of immune complexes and complement. Macrophages infiltrating in later stages may be involved in the healing process.

The affinity of antibody and size of immune complexes are important in production of disease and determining the tissue involved. Diagnosis involves examination of tissue biopsies for deposits of immunoglobulin and complement by immunofluorescence microscopy. The immunofluorescent staining in type III hypersensitivity is granular (as opposed to linear in type II such as seen in Goodpasture's syndrome). The presence of immune complexes in serum and depletion in the level of complement are also diagnostic. Polyethylene glycol-mediated turbidity (nephelometry) binding of C1q and Raji cell test are utilized to detect immune complexes. Treatment includes anti-inflammatory agents.

TYPE IV HYPERSENSITIVITY

Type IV hypersensitivity is also known as cell mediated or delayed type hypersensitivity. The classical example of this hypersensitivity is tuberculin (Montoux) reaction (figure 5) which peaks 48 hours after the injection of antigen (PPD or old tuberculin). The lesion is characterized by induration and erythema.

Tuberculin skin test

Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious diseases (tuberculosis, leprosy, blastomycosis, histoplasmosis, toxoplasmosis, leishmaniasis, etc.) and granulomas due to infections and foreign antigens. Another form of delayed hypersensitivity is contact dermatitis (poison ivy (figure 6), chemicals, heavy metals, etc.) in which the lesions are more papular. Type IV hypersensitivity can be classified into three categories depending on the time of onset and clinical and histological presentation (Table 3).

Mechanisms of damage in delayed hypersensitivity include T lymphocytes and monocytes and/or macrophages. Cytotoxic T cells (Tc) cause direct damage whereas helper T (TH1) cells secrete cytokines which activate cytotoxic T cells and recruit and activate monocytes and macrophages, which cause the bulk of the damage (figure 4). The delayed hypersensitivity lesions mainly contain monocytes and a few T cells.

Major lymphokines involved in delayed hypersensitivity reaction include monocyte chemotactic factor, interleukin-2, interferon-gamma, TNF alpha/beta, etc.

Diagnostic tests in vivo include delayed cutaneous reaction (e.g. Montoux test (figure 5)) and patch test (for contact dermatitis). In vitro tests for delayed hypersensitivity include mitogenic response, lympho-cytotoxicity and IL-2 production.

Corticosteroids and other immunosuppressive agents are used in treatment.

Poison Ivy

Delayed hypersensitivity reactions

Typeeacti

Table 5 - Comparison of Different Types of hypersensitivity

characteristics

type-I(anaphylactic)

type-II(cytotoxic)

type-III(immune complex)

type-IV(delayed type)

antibody IgE IgG, IgM IgG, IgM None

antigen exogenous cell surface soluble tissues & organs

response time

15-30 minutes

minutes-hours 3-8 hours 48-72

hours

appearance weal & flare lysis and necrosis

erythema and edema, necrosis

erythema and induration

histologybasophils and eosinophil

antibody and complement

complement and neutrophils

monocytes and lymphocytes

transferred antibody antibody antibody T-cells

with

examplesallergic asthma, hay fever

erythroblastosisfetalis, Goodpasture's nephritis

SLE, farmer's lung disease 

tuberculin test, poison ivy, granuloma

on time

Clinical appearance

Histology

Antigen and site